JPH083162A - Imidazopyridine derivative and process for producing the same - Google Patents

Abstract

(57) [Summary] [Structure] General formula [Chemical formula 15] [In the formula, R ¹ is a lower alkyl group, R ² is a lower alkanoyl group, and R ³ and R ⁴ represent a lower alkyl group, or are alkylene groups having 3 to 6 carbon atoms which are bonded to each other at the terminals. Forming an imidazopyridine derivative or a pharmaceutically acceptable salt thereof. [Effect] This compound exhibits an excellent angiotensin II antagonistic action and is useful as a prophylactic / therapeutic agent for hypertension.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an imidazopyridine derivative having an antihypertensive effect and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II is a physiologically active peptide consisting of 8 amino acids in which angiotensin I is mainly limited in the pulmonary circulation by angiotensin converting enzyme. It contracts vascular smooth muscle and secretes aldosterone in the adrenal cortex. Increases blood pressure by promoting it. Therefore, it is known that an angiotensin II antagonist can be used as a therapeutic agent for hypertension.

As an antihypertensive drug based on the above-mentioned mechanism of action, for example, JP-A-5-279361 discloses 2-lower alkyl-5-lower alkanoyl-3- (substituted biphenylyl) methyl-4,5,6,7-tetrahydro. Imidazo [4,5
-C] Pyridine-4-carboxylic acid and other imidazopyridine derivatives or pharmacologically acceptable salts thereof are described.

However, the above-mentioned known compounds have poor absorption in the gastrointestinal tract when the drug is orally administered, or even if the absorption in the gastrointestinal tract is high, the absorbed compound is unlikely to be an active substance in plasma. Because it was a thing,
There has been a demand for a compound that is well absorbed in the gastrointestinal tract and, immediately after being absorbed, becomes an active form in plasma and exhibits an excellent pharmacological action.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel imidazopyridine derivative which is well absorbed in the digestive tract, rapidly becomes an active substance, exhibits a strong angiotensin II antagonistic action, and is more useful as an antihypertensive drug. It is a thing.

[0006]

The present invention has the general formula [I]

[0007]

Embedded image

[In the formula, R ¹ represents a lower alkyl group;
² represents a lower alkanoyl group, R ³ and R ⁴ represent a lower alkyl group, or they are bonded to each other at their terminals and have 3 carbon atoms.
To form an alkylene group of 6] or a pharmacologically acceptable salt thereof.

Of the object [I] of the present invention, a particularly preferred compound is 2-n-propyl-5-acetyl-
3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid
(3-Pentyl) oxycarbonyloxymethyl ester and 2-n-propyl-5-acetyl-3- [2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / cyclohexyloxycarbonyloxymethyl ester To be

The object [I] of the present invention can be used in medicinal use in the free form or in the form of its pharmacologically acceptable salt. As the pharmacologically acceptable salt, for example, hydrochloride can be preferably used because of its excellent crystallinity.

The object [I] of the present invention may have optical isomers based on an asymmetric carbon atom, and the present invention includes both these optical isomers and mixtures thereof.

The object [I] of the present invention and a pharmaceutically acceptable salt thereof are suitable for oral administration, but can of course also be administered parenterally, and can be orally or parenterally administered. It can be mixed with an excipient suitable for administration and used as a pharmaceutical preparation. Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Further, for parenteral administration, it can be used in the form of injection.

The dose varies depending on the age, weight, condition of the patient or degree of disease, but the daily dose is usually 0.01 to 10 mg / kg in the case of oral administration,
Particularly, 0.03 to 5 mg / kg, in the case of parenteral administration, 0.002 to 1 mg / kg, particularly 0.01 to 5 mg / kg.
It is preferably 0.3 mg / kg.

According to the present invention, the target [I] is represented by the general formula [II]

[0015]

[Chemical 6]

[Wherein Y represents a hydrogen atom or a protecting group, and other symbols have the same meanings as described above], a salt thereof or a reactive derivative at the carboxyl group thereof and the general formula [III].

[0017]

[Chemical 7]

[In the formula, X represents a reactive residue, and other symbols have the same meanings as described above. ] When Y is a protecting group, it can be produced by removing the protecting group from the product after the reaction with the compound represented by

The reaction of compound [II], a salt thereof or a reactive derivative of the carboxyl group thereof with compound [III] can be carried out according to a conventional method.

Examples of the salt of the compound [II] include alkali metal salts, alkaline earth metal salts, organic amine salts and the like. As the reactive derivative at the carboxyl group of the compound [II], for example, corresponding acid halide, acid anhydride, active ester and the like can be preferably used. Further, as the reactive residue of the compound [III], a halogen atom (chlorine atom, bromine atom, iodine atom, etc.) can be preferably used.

For example, the reaction of the free compound [II] or a salt thereof with the compound [III] can be carried out in the presence of a deoxidizing agent. Examples of the deoxidizing agent include alkali metal carbonates (eg potassium carbonate), alkali metal hydrides (eg sodium hydride, potassium hydride etc.) or alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium t). -Butoxide etc.), organic amine (eg trialkylamine, pyridine etc.), alkali metal bicarbonate (eg sodium hydrogencarbonate, potassium hydrogencarbonate etc.) and the like can be used.

These reactions are carried out in a suitable solvent (ether solvent such as dioxane or tetrahydrofuran, di-lower alkylformamide, di-lower alkyl sulfoxide, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, chloroform, methylene chloride) under cooling to heating. For example, -30 ° C. to 100 ° C., particularly -10 ° C. to room temperature can be suitably used.

When the compound produced by the above reaction has a protecting group, the protecting group can be easily removed by a conventional method. Examples of the protecting group include a trityl group, a tri-lower alkylsilyl group, a cyano lower alkyl group, a lower alkoxybenzyl group and the like.

The object [I] of the present invention is represented by the general formula [IV]

[0025]

Embedded image

[In the formula, symbols have the same meanings as described above. ]
Or a salt thereof and a general formula [V]

[0027]

[Chemical 9]

[In the formula, X ¹ represents a reactive residue, and other symbols have the same meanings as described above. ] When Y is a protecting group, it can be produced by reacting with a compound represented by the above or a salt thereof and removing the protecting group.

Further, the target compound [I] has the general formula [VI]

[0030]

[Chemical 10]

[In the formula, symbols have the same meanings as described above. ]
Or a salt thereof and a compound of the general formula [VII]

[0032]

[Chemical 11]

[In the formula, symbols have the same meanings as described above. ]
The compound of the general formula [VIII]

[0034]

[Chemical 12]

[In the formula, symbols have the same meanings as described above. ]
A compound of the general formula [IX]

[0036]

[Chemical 13]

[Wherein the symbols have the same meanings as defined above], a salt thereof or a reactive derivative thereof is reacted, and when Y is a protecting group, the protecting group is removed. It can be manufactured.

The reaction between the starting compounds [IV] and [V] is
It can be carried out in the presence of an alkali metal hydride or an alkali metal alkoxide, or in the presence of a deoxidizing agent. Further, specific examples of the reactive residue represented by X ¹ in the compound [V] include a halogen atom and the like.

When the reaction is carried out in the presence of an alkali metal hydride or an alkali metal alkoxide, examples of the alkali metal hydride include sodium hydride,
Examples thereof include potassium hydride, and examples of the alkali metal alkoxide include sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like. The reaction is carried out in a suitable solvent under cooling to heating, for example, at −30.
C. to 50.degree. C., especially from -10.degree. As the solvent, for example, di (lower alkyl) formamide, di (lower alkyl) sulfoxide, di (lower alkyl) acetamide, lower alkanol and the like can be used.

When the reaction is carried out in the presence of a deoxidizing agent, an alkali metal carbonate or the like can be used as the deoxidizing agent. The reaction suitably proceeds in a suitable solvent under cooling to heating, for example, at -10 ° C to 100 ° C. As the solvent, for example, acetone, dimethylformamide, dimethylsulfoxide or the like can be used.

In the reaction, the desired product [I] may be obtained as a mixture of two position isomers formed by reacting with the compound [V] at the 1-position or 3-position of the imidazopyridine ring of the compound [IV]. In this case, each isomer can be separated by a conventional method such as a silica gel column chromatography method or a recrystallization method.

The reaction between the starting compounds [VI] and [VII] can be carried out in the presence or absence of an acid or a base. When the reaction is carried out in the presence of an acid or a base, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid and fumaric acid, and examples of the base include: Inorganic bases such as alkali metal carbonates and hydrogen carbonates can be used. The reaction suitably proceeds in a suitable solvent under cooling to heating, for example, at 10 ° C. to 100 ° C., particularly at room temperature to the boiling point of the solvent. As the solvent, for example, water or a lower alkanol, tetrahydrofuran, dioxane, a mixture of these and water, or the like can be used.

The reaction of the compound [VIII] obtained by the reaction of the starting compounds [VI] and [VII] with the starting compound [IX] can be carried out according to a conventional method. For example, the reaction can be carried out in the presence or absence of a base or a dehydration condensation agent.

The compound [IX] can also be used as its reactive derivative, for example, its acid anhydride or acid halide.

When the reaction is carried out in the presence of a base,
As the base, any conventional base can be used,
In particular, organic bases such as tri-lower alkylamine, pyridine and 4-di (lower alkyl) aminopyridine, and inorganic bases such as alkali metal hydrogen carbonate, alkali metal carbonate and alkali metal hydroxide are preferable. The reaction is carried out in a suitable solvent,
Under cooling to heating, for example, −30 ° C. to 100 ° C., especially −
The process suitably proceeds from 10 ° C. to the boiling point of the solvent. As the solvent, for example, methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, ether, or a mixture of these and water can be used.

When the reaction is carried out in the presence of a dehydration condensing agent, examples of the dehydration condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and benzotriazole-1-. Iloxytris (dimethylamino) phosphonium hexafluorophosphate or the like can be used, and further, hydroxybenztriazole, N-hydroxysuccinimide, or the like can be used together as a reaction aid. The reaction suitably proceeds in a suitable solvent under cooling to heating, for example, at −10 ° C. to 80 ° C., especially near room temperature. Examples of the solvent include methylene chloride,
Chloroform, di-lower alkylformamide, acetonitrile, tetrahydrofuran and the like can be used.

In each of the above reactions, each starting compound can be used as it is or in the form of its salt. Examples of the salt of compound [IV] include, for example, hydrochloride,
Examples thereof include hydrobromide and oxalate. Examples of the salt of compound [V] include alkali metal salts and the like. Examples of the salt of compound [VI] include hydrochloride, hydrobromide, oxalate and the like. Also,
Examples of the salt of compound [VIII] include alkali metal salts, alkaline earth metal salts, heavy metal salts, organic amine salts,
Examples thereof include inorganic acid salts and organic acid salts, and examples of the salt of the compound [IX] include alkali metal salts and alkaline earth metal salts. In addition, compound [VII] can also be used in the reaction as a hydrate or alcoholate thereof.

When the compound [I] thus obtained is a racemate, the racemic compound [I] can be easily optically resolved according to a conventional method.

Raw material compounds [II] and [VI] of the present invention
Can be produced according to the method described in JP-A-5-279361.

The starting compound [IV] is disclosed in JP-A-61-
It can be produced according to the method described in 167687 or JP-A-2-101062.

The starting compound [III] can be produced according to the method described in Yamanouchi Kenpo Vol. 2, p. 95 (1974). Among the raw material compounds [III], the raw material compound [III] in which X is a chlorine atom is obtained by reacting methyl chloroformate with sulfuryl chloride and the obtained monochloromethyl chloroformate and the general formula [X].

[0052]

Embedded image

It can be produced by reacting with an alcohol compound represented by the formula [wherein the symbols have the same meanings as described above].

In the present specification, the lower alkyl group represents one having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and the lower alkanoyl group represents 2 to 6 carbon atoms, preferably 2 carbon atoms. ~ 4 is represented.

As the alkyl group having 1 to 4 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl group, etc., and the alkanoyl group having 2 to 4 carbon atoms includes acetyl, propionyl, butyryl, isobutyryl group, etc., and alkylene group having 3 to 6 carbon atoms. Examples thereof include a trimethylene group, a tetramethylene group, a pentamethylene group and a hexamethylene group.

[0056]

【Example】

Example 1 (1) 2-n-propyl-5-acetyl-3- [2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester / 1/2 fumarate 300 g was suspended in a mixed solution of 2 liters of chloroform and 1 liter of water, and 50 g of sodium hydrogen carbonate was added to neutralize the mixture, and 2-n-propyl-5-
Acetyl-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-
270 g of tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester are obtained.

Then, 270 g of this product was added to chloroform 1.
Dissolve in 5 liters, add 65 g of triethylamine and 158 g of trityl chloride, and stir at room temperature overnight. After the reaction solution was washed and dried, the solvent was distilled off and recrystallized from an ethanol-ether mixed solution to give 2-n-propyl-5-acetyl-3- [2 '-(1-trityl-1H-tetrazole-5. -Yl) biphenyl-4-yl] methyl-4,
325.8 g of 5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester is obtained.

M. P. 188-189 ° C (decomposition) FAB-MS (m / z): 742 (M + H), 243
(Base) NMR (CDCl ₃ ) δ: 0.85 and 0.96 (both t, J = 7.3, 3H in total), 1.73 and 2.
20 (both s, 3H in total).

(2) 318 g of this product was suspended in a mixed solution of 2 liters of ethanol and 200 ml of tetrahydrofuran, a solution of 20.0 g of sodium hydroxide in 20 ml of water was added, and the mixture was stirred overnight at room temperature. Then, the solvent is distilled off, 2 liters of chloroform is added, and after washing and drying, the solvent is distilled off. The residue was triturated with ether to give 2-n-propyl-
5-Acetyl-3- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-
c] 319 g of pyridine-4-carboxylic acid are obtained.

FAB-MS (m / z): 728 (M +
1), 243 (base) NMR (DMSO-d6) δ: 0.69 and 0.79
(Both t, J = 7.4, total 3H), 1.56 and 2.02 (both s, total 3H).

(3) This product (2.92 g) was dissolved in dimethylformamide (30 ml), potassium carbonate (0.83 g) was added and the mixture was ice-cooled, and 3-pentyloxycarbonyloxymethyl chloride (0.87 g) in dimethylformamide (5 ml) was added dropwise. To do. After the dropping, the temperature is returned to room temperature and the mixture is stirred overnight. After adding ethyl acetate, washing and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1) to give 2-n-propyl-5-. Acetyl-3- [2 '-(1-trityl-
1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid-3-pentyloxycarbonyloxymethyl ester 2. 95 g are obtained as caramel.

FAB-MS (m / z): 872 (M +
H), 243 (base) NMR (CDCl ₃ ) δ: 4.60 (1H, quin
t), 5.18 (2H, ABq), 5.61 (2H, A
Bq).

(4) To 2.92 g of this product was added 20 ml of 85% formic acid under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. The reaction solution is diluted with ice water, insoluble materials are filtered off and washed. Then, the mixture is neutralized with saturated sodium hydrogen carbonate under ice cooling, extracted with chloroform, washed and dried, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1) to give 2-n-
Propyl-5-acetyl-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-
4,5,6,7-tetrahydroimidazo [4,5-c]
2.09 g of pyridine-4-carboxylic acid-3-pentyloxycarbonyloxymethyl ester is obtained as a caramel. Further, 0.50 g of this product is dissolved in ethanol, 27% hydrogen chloride-ethanol solution is added, and the solvent is distilled off under reduced pressure. The residue was recrystallized from an ethanol-ether mixed solution to give 2-n-propyl-5-acetyl-3-
[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid-3-
0.31 g of pentyloxycarbonyloxymethyl ester hydrochloride is obtained.

M. P. : 198-200 ° C (decomposition) FAB-MS (m / z): 630 (M + H), 207.
(Base) NMR (DMSO-d6) δ: 4.54 (1H, qui)
nt).

Examples 2-3 (1) 2-n-propyl-5-obtained in Example 1- (2)
Acetyl-3- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-
4,5,6,7-tetrahydroimidazo [4,5-c]
Pyridine-4-carboxylic acid and corresponding starting compound [III]
Is treated in the same manner as in Example 1- (3) to give the compounds shown in Table 1 below.

[0066]

[Table 1]

(2) By treating the above product in the same manner as in Example 1- (4), the compounds shown in Table 2 below are obtained.

[0068]

[Table 2]

Reference Example 1 Methyl chloroformate 25.0 g, sulfuryl chloride 35.
7 g and α, α'-azobisisobutyronitrile 100
The mg mixture is heated to reflux for 8 hours. Hexane 1 after cooling
Dilute with 50 ml and cool to 3-pentanol 24.0
Add g.

Pyridine (42.0 g) was added dropwise over 20 minutes with ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction, 200 ml of hexane is added, washed with water, dried and filtered, and then the solvent is distilled off.

The residue was distilled under reduced pressure to obtain 26.3 g of 3-pentyloxycarbonyloxymethyl chloride.

B.p. 102-105 ° C. (34 mmHg) Reference Examples 2-3 Methyl chloroformate, sulfuryl chloride and the corresponding alcohol compound [X] were treated in the same manner as in Reference Example 1 to give the compounds shown in Table 3 below. obtain.

[0073]

[Table 3]

[0074]

INDUSTRIAL APPLICABILITY The imidazopyridine derivative [I] and the pharmacologically acceptable salt thereof, which are the objects of the present invention, have a more excellent angiotensin II antagonistic action as compared with conventionally known imidazopyridine derivatives, and have high blood pressure. Can be used as a therapeutic and / or prophylactic agent for For example,
When the antihypertensive effect was investigated in hypertensive model rats, 2-n-propyl-5-acetyl-3-, which is the object of the present invention, was investigated.
[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid. (3
-Pentyl) oxycarbonyloxymethyl ester showed about 3 times better action compared to the corresponding free carboxylic acid compound and methyl ester compound.

Furthermore, since the object of the present invention [I] and its pharmacologically acceptable salts are well absorbed in the digestive tract and quickly become active bodies, they show high blood concentration and are safe and safe. It can be used appropriately.

In addition, since the pharmacologically acceptable salt (particularly the hydrochloride) of the object [I] of the present invention has excellent crystallinity, it can be isolated in high purity with almost no impurities. it can. In addition, since the target compound [I] and its pharmaceutically acceptable salt are stable against temperature, light, etc., they can be more advantageously used as therapeutic and / or preventive agents for hypertension.

The object [I] of the present invention and the pharmaceutically acceptable salts thereof have low toxicity and high safety.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masakazu Mizobe 15-1-310 Makitacho, Takatsuki City, Osaka Prefecture

Claims (5)

[Claims] 1. A compound of the general formula [I] [In the formula, R ¹ represents a lower alkyl group, R ² represents a lower alkanoyl group, R ³ and R ⁴ represent a lower alkyl group, or an alkylene group having 3 to 6 carbon atoms which is bonded to each other at the terminals. Forming an imidazopyridine derivative or a pharmaceutically acceptable salt thereof. 2. 2-n-propyl-5-acetyl-3-
[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid. (3
-Pentyl) oxycarbonyloxymethyl ester or a pharmacologically acceptable salt thereof. 3. 2-n-propyl-5-acetyl-3-
[2 ′-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid cyclohexyloxycarbonyloxymethyl Esters or pharmacologically acceptable salts thereof. 4. The compound according to claim 1, wherein the pharmaceutically acceptable salt is hydrochloride. 5. A compound represented by the general formula [II]: [In the formula, R ¹ represents a lower alkyl group, R ² represents a lower alkanoyl group, and Y represents a hydrogen atom or a protective group.]
And a salt thereof or a reactive derivative at a carboxyl group thereof and a compound represented by the general formula [III]: [In the formula, X represents a reactive residue, R ³ and R ⁴ each represent a lower alkyl group, or R ³ and R ⁴ are bonded to each other at the terminals and have 3 carbon atoms.
Forming an alkylene group of ~ 6], and when Y is a protecting group, the protecting group can be removed from the product, and if desired, the product can be pharmacologically acceptable. A salt of the general formula [I], which is characterized as a salt [In the formula, symbols have the same meanings as described above. ] The manufacturing method of the imidazo pyridine derivative shown by these or its pharmacologically acceptable salt.